Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam‐controlled randomized clinical trial

Grunebaum, Michael F.; Ellis, Steven P.; Keilp, John G.; Moitra, Vivek K.; Cooper, Thomas B.; Marver, Julia E.; Burke, Ainsley K.; Milak, Matthew S.; Sublette, M. Elizabeth; Oquendo, María A.; Mann, J. John

doi:10.1111/bdi.12487

Cited by 143 publications

(114 citation statements)

References 41 publications

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“…Somewhat surprisingly, plasma BDNF levels were not associated with responder class. Previous studies of bipolar, but not MDD, samples found that plasma BDNF levels were associated with SI response after ketamine (Grunebaum, 2017; Grunebaum et al, 2017), suggesting that the mixed diagnostic composition of this study may explain differences from previous work. Studies exploring the relationship between BDNF and antidepressant response to ketamine have also yielded mixed findings (Haile et al, 2014; Machado-Vieira et al, 2009).…”

Section: Discussioncontrasting

confidence: 66%

“…Further study is needed to determine which of these approaches will prove more fruitful. Complete remission of SI has previously been used as an outcome measure in clinical trials and in a meta-analysis of ketamine’s efficacy (Grunebaum et al, 2017; Grunebaum et al, 2018; Wilkinson et al, 2017), as well as in a study examining the relationship between SI response to ketamine and changes in nocturnal wakefulness (Vande Voort et al, 2017). One strength of the present study is that this data-driven approach provides classifications that directly reflect the phenomena under study as they are, as opposed to what they should be.…”

Section: Discussionmentioning

confidence: 99%

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Characterizing the course of suicidal ideation response to ketamine

Ballard

Yarrington

Farmer

et al. 2018

Journal of Affective Disorders

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Background: No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI response to ketamine. Methods: Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic (0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture modeling to generate SI response classes, and class membership predictors were evaluated using multinomial logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers. Results: The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders (44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1. Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to Remitters rather than Responders. Limitations: Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma, rather than CSF, markers were used. Conclusion: The results underscore the heterogeneity of SI response to ketamine and its potential independence from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic SI were less likely to respond or remit post-ketamine.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Characterizing the course of suicidal ideation response to ketamine

Ballard

Yarrington

Farmer

et al. 2018

Journal of Affective Disorders

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“…As mentioned previously, ketamine has a rapid and long-lasting antidepressant effect in both MDD and BD (Grunebaum et al, 2017;Vande et al, 2017;Kadriu et al, 2018). Our results in this study suggest that ketamine also has a significant improvement in POD, and this beneficial effect could be totally attenuated by TrkB antagonist ANA-12, suggesting that BDNF-TrkB signaling plays an important role in ketamine exerting antidepressant effects in POD.…”

Section: Discussionsupporting

confidence: 78%

Ketamine Alleviates Postoperative Depression-Like Symptoms in Susceptible Mice: The Role of BDNF-TrkB Signaling

Luo

Duan

et al. 2020

Front. Pharmacol.

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Patients are more likely to suffer from central nervous system (CNS) complications after anesthesia and surgery. However, postoperative depression (POD) has not yet received sufficient attentions, and its pathogenesis and therapeutic strategies remain poorly understood. We here aimed to investigate whether brain derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling plays an important role in POD. BDNF-TrkB signaling was altered in brain and peripheral tissues, including medial prefrontal cortex (mPFC), hippocampus, liver, and muscle, among control, POD susceptible, and resilient groups. Additionally, we demonstrated that 7,8dihydroxyflavone (7,8-DHF), a TrkB agonist, could exert its pharmacologic property to alleviate POD-like symptoms. More importantly, ketamine, a non-competitive N-methyl-Daspartic acid (NMDA) receptor antagonist, also has significant antidepressant effects in POD model, associating with the improving effects on levels of BDNF-TrkB signaling in brain and peripheral tissues. Interestingly, the beneficial effects of ketamine on POD-like symptoms are fully attenuated by a TrkB antagonist. These findings suggest that abnormal expressions of BDNF-TrkB signaling in brain and peripheral tissues are implicated in the pathogenesis of POD, and that therapeutic agents targeting BDNF-TrkB, particularly ketamine, could favor the beneficial effects for POD.

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“…At least 2 RCTs, 18,19 not included in the meta-analyses discussed, 13,15 have recently been published. Both RCTs recruited patients with clinically significant suicidal ideation, operationalized as a Scale for Suicidal Ideation (SSI) score of at least 4.…”

Section: Recent Randomized Controlled Trials Of Ketamine In Patients mentioning

confidence: 99%

“…In the first RCT, 18 16 patients with bipolar depression and clinically significant suicidal ideation were randomized to receive IV ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg); ongoing psychotropics, barring benzodiazepines, were continued unchanged during the study. One day after treatment, SSI scores attenuated substantially and nearsignificantly more with ketamine than with midazolam.…”

Section: Recent Randomized Controlled Trials Of Ketamine In Patients mentioning

confidence: 99%

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk

Andrade

2018

J. Clin. Psychiatry

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A growing body of literature suggests that ketamine, administered in subanesthetic doses, has early-onset antidepressant action in patients with severe and even treatment-refractory depression. Many case reports, open-label studies, and randomized controlled trials (RCTs) suggest that ketamine may have dramatic antisuicidal effects, as well. This article examines the benefits of ketamine in patients with suicidal ideation with particular focus on the findings of recent RCTs and meta-analyses. Important findings are that a single dose of ketamine is associated with antisuicidal benefits that emerge within an hour of administration and persist for up to a week. The benefits are seen in patients with mild as well as clinically significant suicidal ideation. The benefits are observed in midazolam- as well as saline-controlled trials. Effect sizes are medium to large. The improvement in suicidal ideation is only partly explained by improvement in depression severity. It is concluded that there is consistent evidence that a single dose of ketamine has dramatic antisuicidal action that emerges almost immediately after dosing and persists for at least a week. The short- and intermediate-term safety and efficacy of ketamine as a crisis intervention treatment for suicidal patients merit study. Areas that need research are outlined.

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Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam‐controlled randomized clinical trial

Cited by 143 publications

References 41 publications

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine

Ketamine Alleviates Postoperative Depression-Like Symptoms in Susceptible Mice: The Role of BDNF-TrkB Signaling

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk

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